DNA topoisomerase I (Top1) is believed to be an important target for the design of novel antitumor drugs. It is a ubiquitous and essential nuclear enzyme for DNA replication and transcription. As a class, the Top1 inhibitors in the camptothecin (1) family (CPTs) have been reported to suffer from poor water-solubility, high toxicity, and metabolic instability. Subsequent efforts to improve the limitations of 1 have lead to topotecan (2) and irinotecan (3).
However, is believed herein that additional improvements in this class of molecules is needed. For example, this family made be limited by the E-ring of the CPTs, which contains an α-hydroxylactone that opens to a hydroxycarboxylate that binds tightly to serum albumin; and the drug-target interaction, which is reversible and has to be maintained long enough to convert Top1 cleavage complexes into DNA damage. In addition, it has been reported that several Top1 resistance mutations such as Asn722Ser and Arg364His occur; tumor cells that over-express drug efflux pumps are becoming resistant to CPTs; and the occurrence of side effects caused by CPTs, which may limit the doses that can be safely administered and, therefore, antitumor efficacy.
It has been discovered that the norindenoisoquinolines described herein are potent cytotoxic agents, and modulators of topoisomerase I.
In one illustrative embodiment of the invention, compounds of the following formula are described herein
and pharmaceutically acceptable salts thereof, wherein
RA represents four substituents each independently selected from the group consisting of hydrogen, halo, azido, and nitro, and hydroxy, amino, and thio, and derivatives thereof, and acyl, sulfoxyl, sulfonyl, phosphinyl, and phosphonyl, and CO2H, SO2H, SO3H, PO2H, and PO3H, and derivatives thereof, and alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or RA includes at least two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle;
RD represents three substituents each independently selected from the group consisting of hydrogen, halo, azido, and nitro, and hydroxy, amino, and thio, and derivatives thereof, and acyl, sulfoxyl, sulfonyl, phosphinyl, and phosphonyl, and CO2H, SO2H, SO3H, PO2H, and PO3H, and derivatives thereof, and alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, arylalkenyl, and arylalkynyl, each of which is optionally substituted; or RD includes at least two adjacent substituents that are taken together with the attached carbons to form an optionally substituted heterocycle;
X and Y are each independently selected from the group consisting of hydrogen, and hydroxy, amino, hydroxylamino, and hydrazino, and derivatives thereof, and alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, and arylalkyl, each of which is optionally substituted; or X and Y are taken together with the attached carbon to form carbonyl, imino, oximino, hydrazono, or alkylidenyl, each of which is optionally substituted; and
W is a hydrophilic group.
In another illustrative embodiment, compounds of the following formula are described herein
and pharmaceutically acceptable salts thereof, wherein RA, RD, W, X, and Y are as defined in the various embodiments described herein; and
RN is hydrogen, or hydroxy, amino, or thio, or a derivative thereof, or acyl, sulfoxyl, sulfonyl, phosphinyl, or phosphonyl, or CO2H, SO2H, SO3H, PO2H, or PO3H, or a derivative thereof, or alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, arylalkyl, arylalkenyl, or arylalkynyl, each of which is optionally substituted; and
(L−) is a pharmaceutically acceptable anion.
Without being bound by theory, it is believed herein that the compounds described herein may be highly efficacious because of the increased water solubility provided by the group W.
It has also been discovered that the norindenoisoquinolines described herein may have different Top1 cleavage patterns than other compounds, such as the CPTs and indenoisoquinolines that have been reported. Without being bound by theory, it is believed herein that this difference may indicate that different cancer cell genes could be targeted more selectively with norindenoisoquinolines.